DESCRIPTION: The present proposal seeks to answer fundamental questions about mammalian olfactory nerve synapses. Despite advances in our understanding of the circuitry and synaptic physiology in the main olfactory bulb (MOB), many questions about neurotransmission at the first synapse in the olfactory system have not been answered. Primary olfactory neurons in the epithelium terminate in the glomerular layer of MOB where they synapse on the dendrites of mitral cells (MC). Activation of the olfactory nerve (ON) directly activates MCs, the primary relay cell in the olfactory system. However the transmitter(s) and receptors(s) mediating synaptic transmission between the ON and MCs in the mammal are not known. Our new findings in rat MOB slices demonstrate that ON stimulation elicits a rapid, short latency and a delayed excitation of MCs that are differentially blocked by non-NMDA and NMDA receptor antagonists. We propose a set of neurophysiological studies to rigorously rest the hypothesis the glutamate release from ON terminals monosynaptically activates MCs via actions at NMDA and non-NMDA receptors. Our new findings indicate that the NMDA response undergoes long-term potentiation (LTP) after a burst of high frequency ON stimulation in vitro. Rodents have an olfactory recognition memory located at the first relay in this sensory system. Odor memories are acquired with one-trial learning and last for weeks. Our finding of LTP at the ON->MC synapse discloses a mechanism that may underlie the capacity of the olfactory system to form rapid odor-specific memories. A major goal of this proposal, therefore, is to test the hypothesis that high frequency ON activation induces selective LTP of NMDA receptor-mediated responses in vitro and in vivo. The peptide carnosine, and the metal ion zinc, are present in the mammalian ON but have no known physiological function. Our preliminary studies show that zinc selectively attenuates the NMDA receptor-mediated component of MC response to ON simulation. We will test the hypothesis the endogenously released zinc modulates ON-evoked excitation of MCs by inhibiting glutamates actions at the NMDA receptor. Carnosine is co-localized with glutamate in ON terminals. Carnosine is a potent chelator of zinc. We hypothesize that carnosine modulates (i.e.) potentiates the actions of glutamate at the NMDA receptor by binding zinc. We will test this hypothesis. Peptides are preferentially released by high frequency activity. We hypothesize that carnosine release during high frequency ON activity plays a key neuromodulatory role that facilitates the induction of NMDA-receptor-dependent LTP.